&lt;p&gt;New advances in understanding how TSP1 regulates NO signaling this year include discovery that blood pressure regulation and cardiovascular responses to stress are abnormal in TSP1 and CD47 null mice. The null mice exhibit exaggerated hypotensive responses to vasodilators and to autonomic blockade. We showed in the previous year that the absence of TSP1 or CD47 or therapeutic blocking of their interaction enhances tissue recovery from fixed ischemic injuries. We have now extended this to ischemia/reperfusion (I/R) injuries. We showed in mouse liver that tissue damage is minimized by blocking this pathway. Liver function is also preserved in that the characteristic elevation of circulating liver enzymes following ischemia/reperfusion injury can be prevented to antibody blocking of the TSP1/CD47 interaction. This could have therapeutic application in organ transplantation to prevent post-transplantation I/R injuries. We then extended this finding to a rat I/R injury model using temporary ligation of the deep inferior epigastric vessels. Remarkably, protection was seen in this I/R injury even when treatment was delayed until 30 minutes after reperfusion. Because most I/R injuries occur under non-elective conditions, the ability to treat post-injury has obvious clinical advantages. &lt;p&gt;Therapeutic irradiation is an important component of the treatment plan for a majority of cancer patients. Our success in controlling I/R injury responses suggested that TSP1/CD47 signaling may also limit survival of radiation injuries. We found that TSP1 and CD47 null mice are remarkably resistant to soft tissue irradiation. This protection was reproduced in isolated vascular cells from the null mice, indicated that radioprotection is cell-autonomous. Importantly, tumors growing in the null mice were not protected, suggesting that therapeutic blocking of this pathway selectively protects normal but not tumor tissue.&lt;/p&gt; &lt;p&gt;It is important to know whether the ability to antagonize NO/cGMP signaling via CD47 is unique to TSP1. Based on peptide binding studies, others have proposed that CD47 recognizes a sequence that is conserved among all 5 members of the thrombospondin family. However, we found using recombinant forms of TSP1, TSP2, and TSP4 that this activity is specific for TSP1.&lt;/p&gt;&lt;p&gt;We extended our understanding of immune regulation by TSP1 to macrophages and innate immune responses to tumors. Over-expression of TSP1 in melanoma cells causes delayed growth and increased tumor-associated macrophage (TAM) recruitment into xenograft tumors grown in nude mice74. However, TAM can differentiate into either cytotoxic (M1) or tumor growth-promoting (M2) states. Increased iNOS is a hallmark of M1 macrophages, and although M1 cytotoxic macrophages are a minor fraction of the TAM in a melanoma xenograft, their recruitment or differentiation is increased when those tumors express TSP1. In vitro, TSP1 acutely induces expression of plasminogen activator inhibitor-1 (PAI-1), an important regulator of macrophage migration, by human and mouse macrophages. PAI-1 is strongly expressed by TAM in TSP1-overexpressing tumors in vivo, suggesting that TSP1-induced macrophage recruitment is at least partially mediated by PAI-1. Moreover, TSP1 and TSP2 cause a significant increase in phorbol ester-mediated superoxide generation by M1-differentated human monocytic cells, which mediates tumor cell killing, by interacting with a61 integrin through their NH2-terminal domains. TSP1 stimulates killing of breast carcinoma and melanoma cells by M1-polarized macrophages in vitro via this release of ROS. Taken together, these data suggest that TSP1 plays an important role in innate anti-tumor immunity by enhancing recruitment and activation of M1 TAM. Thus, avoiding this innate immune surveillance could provide an additional selective pressure for loss of TSP1 and TSP2 expression during tumor progression.&lt;/p&gt;